Tristan Tay, Gayathri Bommakanti, Elizabeth Jaensch, Aparna Gorthi, Iswarya Karapa Reddy, Yan Hu, Ruochi Zhang, Aatman S Doshi, Sin Lih Tan, Verena Brucklacher-Waldert, Laura Prickett, James Kurasawa, Michael Glen Overstreet, Steven Criscione, Jason Daniel Buenrostro, Deanna A Mele
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引用次数: 0
摘要
在癌症中,慢性抗原刺激会促使效应 T 细胞衰竭,从而限制 T 细胞疗法的疗效。最近的研究表明,表观遗传学的重新布线控制着T细胞从效应T细胞向衰竭状态的转变,并使衰竭T细胞的一个亚群对PD1检查点阻断无反应。在这里,我们描述了一种T细胞衰竭的抗原特异性检测方法,它能产生与人类肿瘤中的T细胞表型和转录相似的T细胞。我们对人类表观遗传调节因子进行了筛选,发现 IKZF1 是 T 细胞衰竭的驱动因子。我们发现,IKZF1 降解剂 iberdomide 能阻止 T 细胞效应增强子的染色质重塑,并保持 AP-1、NF-κB 和 NFAT 的结合,从而防止衰竭。因此,我们的研究发现了IKZF1通过表观遗传学调控驱动T细胞衰竭的作用,为在实体瘤中使用iberdomide预防T细胞衰竭提供了理论依据。
Degradation of IKZF1 prevents epigenetic progression of T cell exhaustion in an antigen-specific assay.
In cancer, chronic antigen stimulation drives effector T cells to exhaustion, limiting the efficacy of T cell therapies. Recent studies have demonstrated that epigenetic rewiring governs the transition of T cells from effector to exhausted states and makes a subset of exhausted T cells non-responsive to PD1 checkpoint blockade. Here, we describe an antigen-specific assay for T cell exhaustion that generates T cells phenotypically and transcriptionally similar to those found in human tumors. We perform a screen of human epigenetic regulators, identifying IKZF1 as a driver of T cell exhaustion. We determine that the IKZF1 degrader iberdomide prevents exhaustion by blocking chromatin remodeling at T cell effector enhancers and preserving the binding of AP-1, NF-κB, and NFAT. Thus, our study uncovers a role for IKZF1 as a driver of T cell exhaustion through epigenetic modulation, providing a rationale for the use of iberdomide in solid tumors to prevent T cell exhaustion.
Cell Reports MedicineBiochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)
CiteScore
15.00
自引率
1.40%
发文量
231
审稿时长
40 days
期刊介绍:
Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine.
Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.